Halogenobenzyl aminopropionic acid derivatives

ABSTRACT

A halogenobenzylaminopropionic acid derivative represented by the following formula (1): 
                 
 
or a pharmaceutically acceptable salt of the derivative, and a drug containing the same as an active ingredient for treating diabetes, hyperlipidemia, or similar pathological conditions.

This application is a 371 of PCT/JP02/13573 filed Dec. 26, 2002.

TECHNICAL FIELD

The present invention relates to a halogenobenzylaminopropionic acidderivative which is useful as a preventive or therapeutic agent fordiabetes and hyperlipidemia, and to a drug containing the derivative asan active ingredient.

BACKGROUND ART

In recent years, there have been a growing number of patients sufferingfrom lifestyle-related diseases, especially such as diabetes andhyperlipidemia, as the eating habit of Japanese people is increasinglyWesternized and they have less tendency to take exercise than didbefore. Diabetes and hyperlipidemia are known as critically basaldiseases that could cause the development of arteriosclerosis and leadto ischemic heart diseases as a result.

Diabetes are classified into type I (insulin-dependent diabetesmellitus, IDDM) and type II (non-insulin-dependent diabetes mellitus,NIDDM). Sufferers of the latter type account for more than 90 percent ofdiabetic patients. In many cases, type II diabetes is complicated byhyperlipidemia. So that most patients with such a complicated type IIdiabetics often develop arteriosclerosis and subsequently ischemic heartdiseases. Recent large-scale clinical studies have shown that the risksof these diseases are remarkably reduced by means of a therapy forlowering blood glucose, as well as by means of a therapy for loweringblood lipid (particularly, a therapy for effectively lowering bloodtriglyceride (hereinafter referred to as “blood TG”)) (SENDCAP study(Diabetes Care (US), American Diabetes Association, 21, 641-648 (1998));and DAIS study (Lancet (UK), Lancet, 357, 905-910 (2001))).

For example, the results of the DAIS study show that, when fenofibrate,which is known as a blood lipid lowering agent, is orally administeredto diabetic patients complicated with hyperlipidemia in which a bloodglucose level is sufficiently controlled, a decrease in average minimumlumen diameter and an increase in constriction degree, which indicatecoronary artery lesion, are significantly suppressed, and a decrease inaverage lumen diameter, which indicates diffuse change, is significantlysuppressed. The results also show a significant decrease in the numberof deaths that were assumed to result from progress of coronary arterydiseases, or a significant decrease in the occurrence of cardiovascularevents. The above results show that sufficient control of blood glucoselevel and blood lipid is effective for treatment of patients with bothtype II diabetes and hyperlipidemia (the number of such patients hasincreased in recent years), and for prevention of arteriosclerosis andischemic heart diseases resulting from arteriosclerosis, which are oftendeveloped by such patients. However, fenofibrate per se is well known toexhibit insufficient effect of lowering the blood glucose level of adiabetic patient. Therefore, demand has arisen for a drug exhibiting ahigh blood lipid lowering effect as well as a blood glucose loweringeffect, which drug can be used as means for effectively treatingpatients with both type II diabetes and hyperlipidemia, and as means forpreventing arteriosclerosis and ischemic heart diseases resulting fromarteriosclerosis, which are developed by such patients.

Meanwhile, suppression of lowering of blood free fatty acid (hereinafterreferred to as “blood FFA”) has been reported to implicate insulinresistance (Khan, et al., Diabetologia (Germany), European Associationfor Study of Diabetes., 39 (Suppl), A53 (1996)).

Aminopropionic acid derivatives having a phenyloxazole structure havebeen reported as compounds exhibiting a blood lipid lowering effect aswell as a blood glucose lowering effect (WO 96/38415, WO 97/31907, andWO 2000/08002).

Adiponectin, which is secreted from human adipose cells to the body, hasbeen known to exhibit the effect of improving insulin resistance, whichis a cause of type II diabetes.

DISCLOSURE OF THE INVENTION

As a result of extensive studies, we have found that ahalogenobenzylaminopropionic acid derivative in which a hydrogen atom ofthe benzene ring of a benzyl group is substituted by a halogen atomexhibits remarkably potent blood glucose lowering effect and blood lipidlowering effect, as compared with a corresponding compound having nosubstituent on the benzene ring of the compound, and that the derivativeis useful as a preventing or therapeutic agent for diabetes,hyperlipidemia, and similar diseases. The present invention has beenaccomplished on the basis of this finding.

Accordingly, the present invention provides ahalogenobenzylaminopropionic acid derivative represented by thefollowing formula (1):

[wherein each of R¹ and R², which may be identical to or different fromeach other, represents a hydrogen atom or a lower alkyl group; R³represents a phenyl group which may have a substituent, a morpholinylgroup, or a pyridinyl group; X represents a halogen atom; n representsan integer of 1 to 5; and A represents an oxygen atom or a sulfur atom];or a pharmaceutically acceptable salt of the derivative.

The present invention also provides a halogenobenzylaminopropionic acidderivative represented by the aforementioned formula (1), or apharmaceutically acceptable salt of the derivative.

The present invention also provides a drug composition comprising ahalogenobenzylaminopropionic acid derivative represented by theaforementioned formula (1) or a pharmaceutically acceptable salt of thederivative, and a pharmaceutically acceptable carrier.

The present invention also provides use of ahalogenobenzylaminopropionic acid derivative or a pharmaceuticallyacceptable salt of the derivative for producing a drug.

The present invention also provides a method for treating diabetesand/or hyperlipidemia, which comprises administering, to a subject inneed thereof, an effective dose of a halogenobenzylaminopropionic acidderivative or a pharmaceutically acceptable salt of the derivative.

BEST MODE FOR CARRYING OUT THE INVENTION

Examples of the lower alkyl group represented by R¹ of formula (1)include C1-C4 linear or branched alkyl groups. Specific examples includea methyl group, an ethyl group, an n-propyl group, an n-butyl group, anisopropyl group, a tert-butyl group, and a sec-butyl group. Of these, amethyl group, an ethyl group, and an n-propyl group are preferred, witha methyl group and an ethyl group being more preferred.

Examples of the lower alkyl group represented by R² include C1-C4 linearor branched alkyl groups. Specific examples include a methyl group, anethyl group, an n-propyl group, an n-butyl group, an isopropyl group, atert-butyl group, and a sec-butyl group. Of these, a methyl group ispreferred.

Examples of the phenyl group which may have a substituent represented byR³ include a phenyl group, a phenyl group substituted by a halogen atom,and a phenyl group substituted by a lower alkyl group which may have ahalogen atom. Examples of the halogen atom include a fluorine atom, achlorine atom, a bromine atom, and an iodine atom. Examples of the loweralkyl group which may have a halogen atom include C1-C4 linear orbranched alkyl groups in which one or more hydrogen atoms may besubstituted by a halogen atom. Of these, a methyl group and atrifluoromethyl group are preferred. No particular limitations areimposed on the number of substituents on the phenyl group, and, when thenumber of the substituents is 2 or more, the substituents may differfrom one another. No particular limitations are imposed on the positionsof the substituents on the phenyl group. Examples of the phenyl groupwhich may have a substituent include a phenyl group, a 2-fluorophenylgroup, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenylgroup, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2-bromophenylgroup, a 3-bromophenyl group, a 4-bromophenyl group, a 2-iodophenylgroup, a 3-iodophenyl group, a 4-iodophenyl group, a 2,3-difluorophenylgroup, a 2,4-difluorophenyl group, a 2,5-difluorophenyl group, a2,6-difluorophenyl group, a 3,4-difluorophenyl group, a3,5-difluorophenyl group, a 2,4,6-trifluorophenyl group, apentafluorophenyl group, a 2-methylphenyl group, a 3-methylphenyl group,a 4-methylphenyl group, a 2,3-dimethylphenyl group, a 2,4-dimethylphenylgroup, a 2,5-dimethylphenyl group, a 2,6-dimethylphenyl group, a3,4-dimethylphenyl group, a 3,5-dimethylphenyl group, a2,4,6-trimethylphenyl group, a 2-trifluoromethylphenyl group, a3-trifluoromethylphenyl group, and a 4-trifluoromethylphenyl group. Ofthese, a phenyl group, a 4-fluorophenyl group, a 4-methylphenyl group,and a 4-trifluoromethylphenyl group are preferred.

Examples of the morpholinyl group represented by R³ include a2-morpholinyl group, a 3-morpholinyl group, and a 4-morpholinyl group,with a 4-morpholinyl group being most preferred.

Examples of the pyridinyl group represented by R³ include a 2-pyridinylgroup, a 3-pyridinyl group, and a 4-pyridinyl group, with a 4-pyridinylgroup being most preferred.

R³ of formula (1) is preferably a phenyl group which may have asubstituent.

Examples of the halogen atom represented by X include a fluorine atom, achlorine atom, a bromine atom, and an iodine atom. Of these, a fluorineatom, a chlorine atom, or a bromine atom is preferred, with a fluorineatom and a chlorine atom being particularly preferred. In formula (1), nrepresents an integer of 1 to 5, and particularly, an integer of 1 to 3is preferred. When n is 2 or more, the halogen atoms may differ from oneanother. No particular limitations are imposed on the position of X onthe corresponding phenyl group. Depending on the number and position ofX, the substituent on the phenyl group assumes various forms. Specificexamples of the substituent include a 2-fluoro group, a 3-fluoro group,a 4-fluoro group, a 2-chloro group, a 3-chloro group, a 4-chloro group,a 2-bromo group, a 3-bromo group, a 4-bromo group, a 2-iodo group, a3-iodo group, a 4-iodo group, a 2,3-difluoro group, a 2,4-difluorogroup, a 2,5-difluoro group, a 2,6-difluoro group, a 3,4-difluoro group,a 3,5-difluoro group, a 2,4,6-trifluoro group, and a pentafluoro group.Of these, a 2-fluoro group, a 4-fluoro group, a 2-chloro group, a4-chloro group, a 4-bromo group, a 2,3-difluoro group, a 2,4-difluorogroup, a 2,6-difluoro group, a 3,4-difluoro group, a 2,4,6-trifluorogroup, and a pentafluoro group are preferred.

Examples of the pharmaceutically acceptable salt of the compoundrepresented by formula (1) of the present invention (hereinafter thecompound may be referred to as “the present compound (1)”) includealkali metal salts such as sodium salts and potassium salts; alkalineearth metal salts such as calcium salts and magnesium salts; inorganicacid salts such as hydrochlorides and sulfates; and organic acid saltssuch as oxalates, malonates, and methanesulfonates.

The present compound (1) has an asymmetric carbon atom, and thus hasoptical isomers attributed to the asymmetric carbon atom. The presentinvention encompasses these optical isomers and mixtures thereof.Particularly, optical isomers having an S configuration are preferred.The present compound (1) also encompasses hydrates and various solvates.The present compound (1) also encompasses all the crystal forms.

Specific examples of the present compound (1) include ethyl3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionate,ethyl3-[4-[2-[5-methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionate,ethyl3-[4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionate,ethyl3-[4-[2-[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionate,methyl3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,3-difluorobenzylamino)propionate,methyl3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,6-difluorobenzylamino)propionate,methyl3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,4,6-trifluorobenzylamino)propionate,methyl3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-chlorobenzylamino)propionate,methyl3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2-chlorobenzylamino)propionate,3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicacid,3-[4-[2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicacid,3-[4-[2-[5-methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicacid,3-[4-[2-[5-methyl-2-(4-trifluoromethylphenyl)-1,3-oxazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicacid,3-[4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicacid,3-[4-[2-[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicacid,3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2-fluorobenzylamino)propionicacid,3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,4-difluorobenzylamino)propionicacid,3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(3,4-difluorobenzylamino)propionicacid,3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,3-difluorobenzylamino)propionicacid,3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,6-difluorobenzylamino)propionicacid,3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,4,6-trifluorobenzylamino)propionicacid,3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(pentafluorobenzylamino)propionicacid,3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-chlorobenzylamino)propionicacid,3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2-chlorobenzylamino)propionicacid,3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-bromobenzylamino)propionicacid,3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-[N-(4-fluorobenzyl)-N-methylamino]propionicacid, and pharmaceutically acceptable salts of these compounds. Opticalisomers of these compounds having an S configuration are more preferred.

The present compound (1) can be produced through the process representedby the following reaction scheme:

(wherein R¹, R², R³, X, n, and A have the same meanings as describedabove, Y represents a substituent which can be subjected to condensationreaction (e.g., a hydroxyl group, a methanesulfonyloxy group, ap-toluenesulfonyloxy group, or a halogen atom), and each of R^(2′) andR⁴ represents a lower alkyl group (the definition of the lower alkylgroup is the same as in the case of R¹)).

When R is a hydrogen atom, step 2 is not performed. When R¹ is ahydrogen atom, step 3 is performed. Steps 1 through 3 will next bedescribed.

Step 1

In this step, the compound of formula (2) is condensed with the compoundof formula (3), to thereby produce the compound of formula (1a). When Yof the compound of formula (3) is a hydroxyl group, the compound offormula (1a) can be produced by subjecting the compound of formula (2)and the compound of formula (3) to a reaction similar to a typicalMitsunobu reaction [e.g., O. Mitsunobu, Synthesis, 1 (1981), TetsutoTsunoda, et al., Journal of Synthetic Organic Chemistry, Japan, 55 (7),631 (1997)]. Specifically, the compound of formula (1a) can be producedby reacting the compound of formula (2) and the compound of formula (3)with a Mitsunobu reagent (e.g., N,N,N′,N′-tetramethylazodicarboxamide)at a reaction temperature of −10° C. to 80° C. for 1 to 48 hours in anaromatic hydrocarbon (e.g., benzene, toluene, or xylene), a halogenatedhydrocarbon (e.g., dichloromethane or chloroform), an ether (e.g.,diethyl ether, tetrahydrofuran, or dioxane), or a mixture of thesesolvents in the presence of a phosphine such as tributylphosphine.

When the compound of formula (3) has a group which is eliminated throughnucleophilic reaction; i.e., when Y is, for example, amethanesulfonyloxy group, a p-toluenesulfonyloxy group, or a halogenatom, the compound of formula (1a) can be produced by subjecting thecompound of formula (2) and the compound of formula (3) to a typicalnucleophilic substitution reaction. Specifically, the compound offormula (1a) can be produced by reacting the compound of formula (2) andthe compound of formula (3) with a base (e.g., metallic sodium, sodiumhydride, sodium hydroxide, metallic potassium, potassium hydride,potassium carbonate, cesium carbonate, or rubidium carbonate) at areaction temperature of −10° C. to the boiling point for 1 to 48 hoursin an aromatic hydrocarbon (e.g., benzene, toluene, or xylene), ahalogenated hydrocarbon (e.g., dichloromethane or chloroform), an ether(e.g., diethyl ether, tetrahydrofuran, or dioxane), an amide (e.g.,dimethylacetamide or dimethylformamide), or a mixture of these solvents(if desired, in the presence of a reaction promoter such as sodiumiodide, tetrabutylammonium halide, ortris[2-(2-methoxyethoxy)ethyl]amine).

Step 2

In this step, the compound of formula (1a) and an alkyl halide aresubjected to a typical nucleophilic substitution reaction, to therebyproduce the compound of formula (1b). Specifically, the compound offormula (1b) can be produced by reacting the compound of formula (1a)and an alkyl halide (e.g., methyl iodide or ethyl iodide) with a base(e.g., metallic sodium, sodium hydride, sodium hydroxide, metallicpotassium, potassium hydride, or potassium carbonate) at a reactiontemperature of −10° C. to the boiling point for 1 to 48 hours in anaromatic hydrocarbon (e.g., benzene, toluene, or xylene), a halogenatedhydrocarbon (e.g., dichloromethane or chloroform), an ether (e.g.,diethyl ether, tetrahydrofuran, or dioxane), an amide (e.g.,dimethylacetamide or dimethylformamide), or a mixture of these solvents(if desired, in the presence of a reaction promoter such as sodiumiodide or tetrabutylammonium halide).

Step 3

In this step, the lower alkyl group represented by R⁴ is eliminated fromthe compound of formula (1b), to thereby produce the present compound(1). When R⁴ of the compound of formula (1b) is a chain alkyl group suchas a methyl group, an ethyl group, or an n-propyl group, the compound offormula (1) can be produced by subjecting the compound of formula (1b)to reaction at a reaction temperature of 0° C. to 100° C. for 1 to 48hours in an alcohol (e.g., methanol or ethanol), an ether (e.g., diethylether, tetrahydrofuran, or dioxane), water, or a mixture of thesesolvents in the presence of a base such as an alkali metal hydroxide(e.g., sodium hydroxide or potassium hydroxide).

When R⁴ of the compound of formula (1b) is, for example, a tert-butylgroup, the compound of formula (1) or a pharmaceutically acceptable saltthereof can be produced by reacting the compound of formula (1b) with anorganic acid such as formic acid, acetic acid, or trifluoroacetic acidor with an inorganic acid such as hydrochloric acid or sulfuric acid ata reaction temperature of 0° C. to 100° C. for 10 minutes to 12 hours inan alcohol (e.g., methanol or ethanol), an ether (e.g., diethyl ether,tetrahydrofuran, or dioxane), or a mixture of these solvents, or in theabsence of a solvent.

The compound of formula (1) of the present invention can be formed intopharmaceutically acceptable salts (with acid or base) by means of acustomary method. The salt form varies in accordance with the type ofthe compound. Examples of the salts include inorganic acid salts such asa hydrochloride, a hydrobromide, a hydroiodide, a sulfate, a nitrate,and a phosphate; organic acid salts such as an acetate, atrifluoroacetate, an oxalate, a fumarate, a maleate, a tartrate, amethanesulfonate, and a p-toluenesulfonate; alkali metal salts such as asodium salt and a potassium salt; and alkaline earth metal salts such asa calcium salt.

The compound of formula (1a) can also be readily produced through thefollowing process:

(wherein R³, R⁴, X, n, and A have the same meanings as described above).

Steps 4 and 5 will next be described.

Step 4

In this step, the compound of formula (4) is condensed with the compoundof formula (5), to thereby produce the compound of formula (6). Reactionis performed by use of, if desired, an acid catalyst (e.g., acetic acid,p-toluenesulfonic acid, or sulfuric acid) and/or a dehydrating agent(e.g., molecular sieves or silica gel). Specifically, the compound offormula (6) can be produced by reacting the compound of formula (4) withthe compound of formula (5) at a reaction temperature of 0° C. to 120°C. for one hour to one week in an alcohol (e.g., methanol or ethanol),an ether (e.g., diethyl ether, tetrahydrofuran, or dioxane), an aromatichydrocarbon (e.g., benzene or toluene), or a mixture of these solvents(if desired, in the presence of an acid catalyst and/or a dehydratingagent).

When the compound of formula (4) is in the form of a salt such as ahydrochloride, preferably, the compound is neutralized with an organicbase such as triethylamine or with an inorganic base such as sodiumhydroxide, sodium hydrogencarbonate, sodium carbonate, potassiumhydroxide, potassium hydrogencarbonate, or potassium carbonate, and thethus-neutralized compound is subjected to reaction.

Step 5

In this step, the imine moiety of the compound of formula (6) isreduced, to thereby produce the compound of formula (1a). Specifically,the compound of formula (1a) can be produced by subjecting the compoundof formula (6) to reduction reaction employing a reducing agent (e.g.,sodium borohydride, sodium triacetoxyborohydride, or sodiumcyanoborohydride) or to catalytic reduction reaction (in the presence ofpalladium-carbon) at a reaction temperature of −10° C. to 80° C. for 1to 48 hours in an alcohol (e.g., methanol or ethanol), an ether (e.g.,diethyl ether, tetrahydrofuran, or dioxane), or a mixture of thesesolvents. The compound of formula (1a) can also be produced by means ofa known imine reduction process.

The compound of formula (2) can be readily produced through thefollowing process:

(wherein R⁴, X, and n have the same meanings as described above).

Steps A-1 and A-2 will next be described.

Step A-1

In this step, the compound of formula (5) is condensed with the compoundof formula (7), to thereby produce the compound of formula (8). Reactionis performed by use of, if desired, an acid catalyst (e.g., acetic acid,p-toluenesulfonic acid, or sulfuric acid) and/or a dehydrating agent(e.g., molecular sieves or silica gel). Specifically, the compound offormula (8) can be produced by reacting the compound of formula (5) withthe compound of formula (7) at a reaction temperature of 0° C. to 120°C. for one hour to one week in an alcohol (e.g., methanol or ethanol),an ether (e.g., diethyl ether, tetrahydrofuran, or dioxane), an aromatichydrocarbon (e.g., benzene or toluene), or a mixture of these solvents(if desired, in the presence of an acid catalyst and/or a dehydratingagent).

When the compound of formula (7) is in the form of a salt such as ahydrochloride, preferably, the compound is neutralized with an organicbase such as triethylamine or with an inorganic base such as sodiumhydroxide, sodium hydrogencarbonate, sodium carbonate, potassiumhydroxide, potassium hydrogencarbonate, or potassium carbonate, and thethus-neutralized compound is subjected to reaction.

Step A-2

In this step, the imine moiety of the compound of formula (8) isreduced, to thereby produce the compound of formula (2). Specifically,the compound of formula (2) can be produced by subjecting the compoundof formula (8) to reduction reaction employing a reducing agent (e.g.,sodium borohydride, sodium triacetoxyborohydride, or sodiumcyanoborohydride) or to catalytic reduction reaction (in the presence ofpalladium-carbon) at a reaction temperature of −10° C. to 80° C. for 1to 48 hours in an alcohol (e.g., methanol or ethanol), an ether (e.g.,diethyl ether, tetrahydrofuran, or dioxane), or a mixture of thesesolvents. The compound of formula (2) can also be produced by means of aknown imine reduction process.

The compound of formula (4) can be readily produced through thefollowing process:

(wherein R³, R⁴, A, and Y have the same meanings as described above, R⁵represents an amino protective group, and R⁶ represents a hydrogen atomor an amino protective group, with the proviso that R⁵ and R⁶ maytogether form an amino protective group).

The amino protective group (represented by R⁵ or R⁶) is a generallyknown protective group. Examples of the protective group include anaralkyl group (e.g., a benzyl group, a diphenylmethyl group, or a tritylgroup), a tert-butoxycarbonyl group, and a benzyloxycarbonyl group. WhenR⁵ and R⁶ together form an amino protective group, the protective groupis, for example, a phthaloyl group.

Steps A-3 and A-4 will next be described.

Step A-3

In this step, the compound of formula (9) is condensed with the compoundof formula (3), to thereby produce the compound of formula (10). When Yof the compound of formula (3) is a hydroxyl group, the compound offormula (10) can be produced by subjecting the compound of formula (9)and the compound of formula (3) to a reaction similar to a typicalMitsunobu reaction. Specifically, the compound of formula (10) can beproduced by reacting the compound of formula (9) and the compound offormula (3) with a Mitsunobu reagent (e.g., diisopropylazodicarboxylate) at a reaction temperature of −10° C. to 80° C. for 1to 48 hours in an aromatic hydrocarbon (e.g., benzene, toluene, orxylene), a halogenated hydrocarbon (e.g., dichloromethane orchloroform), an ether (e.g., diethyl ether, tetrahydrofuran, ordioxane), or a mixture of these solvents in the presence of a phosphinesuch as triphenylphosphine.

When the compound of formula (3) has a group which is eliminated throughnucleophilic reaction; i.e., when Y is, for example, amethanesulfonyloxy group, a p-toluenesulfonyloxy group, or a halogenatom, the compound of formula (10) can be produced by subjecting thecompound of formula (9) and the compound of formula (3) to a typicalnucleophilic substitution reaction. Specifically, the compound offormula (10) can be produced by reacting the compound of formula (9) andthe compound of formula (3) with a base (e.g., metallic sodium, sodiumhydride, sodium hydroxide, metallic potassium, potassium hydride,potassium carbonate, cesium carbonate, or rubidium carbonate) at areaction temperature of −10° C. to the boiling point for 1 to 48 hoursin an aromatic hydrocarbon (e.g., benzene, toluene, or xylene), ahalogenated hydrocarbon (e.g., dichloromethane or chloroform), an ether(e.g., diethyl ether, tetrahydrofuran, or dioxane), an amide (e.g.,dimethylacetamide or dimethylformamide), or a mixture of these solvents(if desired, in the presence of a reaction promoter such as sodiumiodide, tetrabutylammonium halide, ortris[2-(2-methoxyethoxy)ethyl]amine).

Step A-4

In this step, the amino protective group (represented by R⁵ and/or R⁶)is eliminated from the compound of formula (10), to thereby produce thecompound of formula (4). When R⁵ and/or R⁶ of the compound of formula(10) are, for example, a tert-butoxycarbonyl group, the compound offormula (4) can be produced by reacting the compound of formula (10)with an organic acid such as formic acid, acetic acid, ortrifluoroacetic acid or with an inorganic acid such as hydrochloric acidor sulfuric acid at a reaction temperature of 0° C. to 100° C. for 10minutes to 12 hours in an alcohol (e.g., methanol or ethanol), an ether(e.g., diethyl ether, tetrahydrofuran, or dioxane), or a mixture ofthese solvents, or in the absence of a solvent.

Meanwhile, when R⁵ and/or R⁶ of the compound of formula (10) are, forexample, an aralkyl group or a benzyloxycarbonyl group, the compound offormula (4) is produced by subjecting the compound of formula (10) tocatalytic hydrogenation. Specifically, the compound of formula (4) canbe produced by subjecting the compound of formula (10) to catalyticreduction reaction (in the presence of palladium-carbon) at a reactiontemperature of −10° C. to 80° C. for 1 to 48 hours in an alcohol (e.g.,methanol or ethanol), an ether (e.g., diethyl ether, tetrahydrofuran, ordioxane), or a mixture of these solvents.

When R⁵ and R⁶ of the compound of formula (10) together form an aminoprotective group (e.g., a phthaloyl group), the compound of formula (4)can be produced by subjecting the compound of formula (10) to reactionat a reaction temperature of 0° C. to 100° C. for 1 to 48 hours in analcohol (e.g., methanol or ethanol), an ether (e.g., diethyl ether,tetrahydrofuran, or dioxane), a halogenated hydrocarbon (e.g.,dichloromethane or chloroform), or a mixture of these solvents in thepresence of a hydrazine compound (e.g., hydrazine) or a primary amine(e.g., methylamine or ethylamine).

The thus-produced present compound (1) or a pharmaceutically acceptablesalt thereof exhibits excellent blood glucose lowering effect and bloodlipid (TG and FFA) lowering effect, as shown in the below-described TestExamples. For example, the present compound (1) or a pharmaceuticallyacceptable salt thereof is useful as drugs for animals (includinghuman), including a preventive or therapeutic agent for diabetes (e.g.,insulin-dependent diabetes mellitus, non-insulin-dependent diabetesmellitus, or gestational diabetes mellitus), a preventive or therapeuticagent for hyperlipidemia (e.g., hypertriglyceridemia,hypercholesterolemia, or hypoHDLemia), an insulin sensitivity enhancingagent, an insulin resistance improving agent, a preventive ortherapeutic agent for impaired glucose tolerance (IGT), and an agent forpreventing progression from impaired glucose tolerance to diabetes. Thepresent compound (1) or a pharmaceutically acceptable salt thereof isalso useful as a preventing or therapeutic agent for, for example,diabetic complications (e.g., neurosis, nephropathy, retinopathy,cataract, macroangiopathy, and osteopenia), obesity, osteoporosis,cachexia (e.g., cancerous cachexia or diabetic cachexia), fatty liver,hypertension, kidney diseases (e.g., diabetic nephropathy andglomerulonephritis), myocardial infarction, angina pectoris, cerebralinfarction, insulin resistant syndrome, syndrome X, perception disorderby hyperinsulinemia, tumor (e.g., prostatic cancer), inflammatorydiseases (e.g., chronic articular rheumatism and spondylosis deformans),and arteriosclerosis (e.g., atherosclerosis).

The present compound (1) or a pharmaceutically acceptable salt thereofmay be incorporated into a pharmaceutically acceptable carrier, and theresultant drug composition may be administered orally or parenterally(e.g., through intravenous or intramuscular injection).

Examples of oral formulations include tablets (including sugar-coatedtablets and film-coated tablets), pills, granules, powders, capsules(including soft capsules), syrups, emulsions, and suspensions. Theseoral formulations can be produced by combining the present compound (1)or a pharmaceutically acceptable salt thereof with one or more additiveswhich are generally employed in the manufacture of drugs, through aknown method. Examples of the additives which may be employed includeexcipients such as lactose, mannitol, and anhydrous calciumhydrogenphosphate; binders such as hydroxypropyl cellulose, methylcellulose, and polyvinyl pyrrolidone; disintegrating agents such asstarch and carboxymethyl cellulose; and lubricants such as magnesiumstearate and talc.

Examples of parenteral formulations include injections. Injectionproducts are produced through a known method; for example, injectionsare produced by dissolving the present compound (1) or apharmaceutically acceptable salt thereof into water for injection asspecified by Japanese Pharmacopoeia. If desired, injections may contain,for example, isotonizing agents such as sodium chloride and bufferagents such as sodium hydrogenphosphate or sodium monohydrogenphosphate.

The daily dose of the present compound (1) for an adult patient differsdepending on, for example, the medical condition, body weight, and ageof the patient, the type of the compound, and the administration route.In the case of oral administration, the daily dose is appropriatelyabout 0.01 to 1,000 mg, preferably about 0.01 to 100 mg. In the case ofparenteral administration, the daily dose is preferably 1/10 to ½ thatin the case of oral administration. The daily dose of the compound maybe appropriately increased or decreased in consideration of, forexample, the medical condition, body weight, and age of the patient.

EXAMPLES

The present invention will next be described in more detail withreference to referential examples, examples, a comparative example, anda test example. However, the present invention should not be construedas being limited to these examples.

Referential Example 1 (S)—N-(4-Fluorobenzyl)tyrosine Ethyl Ester(Referential Compound 1)

An (S)-tyrosine hydrochloride ethyl ester (61.5 g) and triethylamine (42mL) were dissolved in methanol (250 mL), and molecular sieve 4A wasadded thereto. 4-Fluorobenzaldehyde (30 mL) was added dropwise theretoat 0° C., and the mixture was stirred for five hours at roomtemperature. Formation of an imine was confirmed through thin-layerchromatography. After the reaction mixture was cooled in an ice bath,sodium borohydride (10.4 g) was added thereto, and the mixture wasstirred overnight at room temperature. The reaction mixture was filteredby use of celite, and the solvent was distilled off at low temperature.Water was added to the residue, and the mixture was subjected toextraction with chloroform. The organic layer was concentrated and thendiluted with diethyl ether. A diethyl ether solution saturated withhydrogen chloride was added thereto, and the mixture was subjected toextraction with water. A 10-%(w/v) aqueous sodium hydroxide solution wasadded dropwise to the aqueous layer, to thereby adjust the pH of themixture to 12. The resultant mixture was subjected to extraction withdiethyl ether and ethyl acetate, and the solvent was distilled off, tothereby yield 67.3 g of the title compound as a colorless oil.

IRν max (neat): 3382, 2977, 2930, 2846, 1731, 1614, 1515, 1460, 1377,1223, 1107, 1023, 825 cm⁻¹.

¹H-NMR(CDCl₃)δ: 1.25(3H, t, J=7.0 Hz), 2.97(2H, d, J=6.8 Hz), 3.53(1H,t, J=6.8 Hz), 3.69(1H, d, J=13.0 Hz), 3.84(1H, d, J=13.0 Hz), 4.17(2H,q, J=7.0 Hz), 6.74(2H, d, J=8.6 Hz), 6.93-7.04(4H, m), 7.23-7.28(2H, m).

Referential Example 2(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-[N-tert-butoxycarbonyl-(4-fluorobenzyl)amino]propionicAcid (Referential Compound 2)

Under argon atmosphere, Compound 18 (200 mg) was added to 1,4-dioxane (4mL) and water (2 mL), to thereby yield a dispersion solution.Triethylamine (520 μL) and di-tert-butyldicarbonate (214 μL) were addedthereto at 0° C., and the mixture was stirred for one hour at roomtemperature. The solvent was removed under reduced pressure, and theresidue was diluted with chloroform. The organic layer was washed with a10-%(w/v) aqueous citric acid solution, water, and saturated brine anddried over anhydrous sodium sulfate. Subsequently, the solvent wasremoved under reduced pressure, and the thus-obtained crude product wassubjected to purification through silica gel column chromatography(chloroform:methanol=30:1 to 10:1), to thereby yield 199.7 mg of thetitle compound as a colorless amorphous compound.

IRν max(neat): 3060, 2977, 2929, 2874, 2558, 1698, 1654, 1609, 1558,1510, 1458, 1247, 1223, 1155, 1025, 826, 757, 692 cm⁻¹.

¹H-NMR(CDCl₃)δ: 1.26(9H, s), 2.40(3H, s), 3.00(2H, t, J=6.7 Hz),3.13-3.28(2H, m), 3.49-3.77(2H, m), 4.01(1H, brs), 4.23(2H, t, J=6.7Hz), 6.79(2H, d, J=8.3 Hz), 6.85-6.98(6H, m), 7.41-7.43(3H, m), 8.00(2H,brs).

Referential Example 3 Methyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-aminopropionatehydrochloride (Referential Compound 3)

Under argon atmosphere, an L-tert-butoxycarbonyltyrosine methyl ester(15.3 g) and 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethanol (11.6 g) weredissolved in toluene (500 mL), and triphenylphosphine (16.3 g) was addedto the resultant mixture. Diisopropyl azodicarboxylate (11.2 mL) wasadded dropwise thereto under cooling with ice. After completion ofaddition, the mixture was stirred overnight at room temperature. Water(500 mL) was added to the reaction mixture, and the mixture wassubjected to extraction with ethyl acetate. The organic layer was washedwith a 1-mol/L aqueous sodium hydroxide solution, water, and saturatedbrine, and dried over anhydrous sodium sulfate. Subsequently, thesolvent was removed under reduced pressure, to thereby yield a paleyellow syrup. The product was dissolved in dioxane (160 mL), and a1,4-dioxane solution saturated with hydrogen chloride (80 mL) was addeddropwise to the solution, followed by stirring overnight. The solventwas removed under reduced pressure, and acetone (500 mL) was added tothe residue. The precipitate was collected through filtration, washedwith acetone and diisopropyl ether, and dried, to thereby yield 19.2 gof the title compound as a colorless powder.

IRν max(KBr): 3448, 3030, 2856, 2632, 1846, 1732, 1676, 1610, 1577,1512, 1444, 1289, 1245, 1181, 1025 cm⁻¹.

¹H-NMR(CD₃OD)δ: 2.41(3H, s), 2.98-3.22(4H, m), 3.79(3H, s),4.22-4.27(3H, m), 6.93(2H, d, J=8.6 Hz), 7.14(2H, d, J=8.6 Hz),7.48-7.50(3H, m), 7.95-7.98(2H, m).

Example 1Ethyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionate(Compound 1)

To a solution of Referential Compound 1 (6.22 g) in toluene (200 mL),2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethanol (5.97 g) andtributylphosphine (9.8 mL) were added, and the mixture was stirred for30 minutes at room temperature. While the reactor was cooled in an icebath, 1,1′-azobis(N,N-dimethylformamide) (6.75 g) was added theretoportion wise, and the mixture was stirred overnight. Water (200 mL) wasadded to the reaction mixture, and the resultant mixture was subjectedto extraction with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate.Subsequently, the solvent was removed under reduced pressure, and thethus-obtained crude product was subjected to purification through silicagel column chromatography (ethyl acetate:hexane=1:3 to 1:2), to therebyyield 7.73 g of the title compound as a pale yellow oil.

IRν max(neat): 3330, 3060, 3033, 2977, 2929, 1731, 1643, 1611, 1555,1511, 1471, 1373, 1293, 1247, 1219, 1179, 1025 cm⁻¹.

¹H-NMR(CDCl₃)δ: 1.18(3H, t, J=7.1 Hz), 2.37(3H, s), 2.95(2H, d, J=6.6Hz), 3.04(2H, t, J=6.8 Hz), 3.55(1H, t, J=6.6 Hz), 3.75(1H, d, J=13.8Hz), 3.85(1H, d, J=13.8 Hz), 4.12(2H, q, J=7.1 Hz), 4.21(2H, t, J=6.8Hz), 6.80(2H, d, J=8.6 Hz), 6.94-7.06(5H, m), 7.30(1H, dd, J=8.5, 5.7Hz), 7.39-7.44(3H, m), 7.97(2H, d, J=8.1 Hz).

m/z(ESI+): 503(M+H)⁺.

[α]_(D) ²⁹ (CHCl₃): +1.7(c=1.6).

Example 2Ethyl(S)-3-[4-[2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionate(Compound 2)

In the same manner as in Example 1, 232.6 mg of the title compound wasobtained as colorless oil from 187.1 mg of Referential Compound 1 and195.6 mg of 2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethanol.

IRν max(neat): 3335, 3036, 2980, 2928, 2874, 1731, 1644, 1608, 1559,1507, 1471, 1416, 1373, 1298, 1222, 1179, 1156, 1024, 949, 842, 737, 620cm⁻¹.

¹H-NMR(CDCl₃)δ: 1.20(3H, t, J=7.2 Hz), 2.36(3H, s), 2.92-3.02(4H, m),3.47-3.55(1H, m), 3.65-3.74(1H, m), 3.76-3.84(1H, m), 4.12(2H, q, J=7.2Hz), 4.20(2H, t, J=6.8 Hz), 6.80(2H, d, J=8.4 Hz), 6.92-7.01(2H, m),7.07(2H, d, J=8.4 Hz), 7.10(2H, t, J=8.6 Hz), 7.20-7.29(2H, m),7.92-8.00(2H, m).

Example 3Ethyl(S)-3-[4-[2-[5-methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionate(Compound 3)

In the same manner as in Example 1, 219.5 mg of the title compound wasobtained as colorless oil from 200.0 mg of Referential Compound 1 and205.3 mg of 2-[5-methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]ethanol.

IRν max(neat): 3336, 3032, 2924, 1730, 1643, 1612, 1583, 1557, 1511,1470, 1372, 1296, 1245, 1220, 1177, 1020, 948, 824, 761, 731, 621 cm⁻¹.

¹H-NMR(CDCl₃)δ: 1.19(3H, t, J=7.2 Hz), 2.35(3H, s), 2.38(3H, s),2.92-3.02(4H, m), 3.51(1H, t, J=6.4 Hz), 3.70(1H, d, J=12.8 Hz),3.80(0.1H, d, J=12.8 Hz), 4.12(2H, q, J=7.2 Hz), 4.20(2H, t, J=6.8 Hz),6.80(2H, d, J=8.4 Hz), 6.96(2H, dd, J=8.6, 8.6 Hz), 7.06(2H, d, J=8.4Hz), 7.20-7.28(4H, m), 7.85(2H, d, J=8.3 Hz).

Example 4Ethyl(S)-3-[4-[2-[5-methyl-2-(4-trifluoromethylphenyl)-1,3-oxazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionate(Compound 4)

In the same manner as in Example 1, 226.4 mg of the title compound wasobtained as colorless oil from 200.0 mg of Referential Compound 1 and256.3 mg of2-[5-methyl-2-(4-trifluoromethylphenyl)-1,3-oxazol-4-yl]ethanol.

IRν max(neat): 2976, 2930, 1731, 1617, 1509, 1473, 1416, 1323, 1245,1221, 1167, 1127, 1083, 1063, 1016, 849, 714, 670 cm⁻¹.

¹H-NMR(CDCl₃)δ: 1.19(3H, t, J=7.2 Hz), 2.39(3H, s), 2.93-3.02(4H, m),3.46-3.52(1H, m), 3.66(1H, d, J=13.0 Hz), 3.79(1H, d, J=13.0 Hz),4.12(2H, q, J=7.2 Hz), 4.21(2H, t, J=6.6 Hz), 6.80(2H, d, J=8.6 Hz),6.95(2H, dd, J=8.6, 8.6 Hz), 7.07(2H, d, J=8.6 Hz), 7.19-7.25(2H, m),7.67(2H, d, J=8.1 Hz), 8.08(2H, d, J=8.1 Hz).

Example 5Ethyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionate(Compound 5)

In the same manner as in Example 1, 172.0 mg of the title compound wasobtained as colorless oil from 186.0 mg of Referential Compound 1 and192.8 mg of 2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethanol.

IRν max(neat): 3339, 3060, 2976, 2927, 2874, 1730, 1610, 1545, 1509,1462, 1373, 1298, 1243, 1178, 1130, 1029, 970, 824, 762, 690 cm⁻¹.

¹H-NMR(CDCl₃)δ: 1.19(3H, t, J=7.2 Hz), 2.45(3H, s), 2.94-3.01(2H, m),3.18(2H, t, J=7.0 Hz), 3.46-3.55(1H, m), 3.68(1H, d, J=13.4 Hz),3.80(1H, d, J=13.4 Hz), 4.12(2H, q, J=7.2 Hz), 4.29(2H, t, J=7.0 Hz),6.81(2H, d, J=8.4 Hz), 6.96(2H, dd, J=8.6, 8.6 Hz), 7.06(2H, d, J=8.4Hz), 7.21-7.30(2H, m), 7.35-7.44(3H, m), 7.83-7.88(2H, m).

Example 6Ethyl(S)-3-[4-[2-[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionate(Compound 6)

In the same manner as in Example 1, 148.8 mg of the title compound wasobtained as colorless oil from 200.0 mg of Referential Compound 1 and215.8 mg of 2-[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]ethanol.

IRν max(neat): 3330, 2963, 2921, 2857, 1731, 1610, 1512, 1455, 1374,1300, 1268, 1231, 1179, 1118, 1026, 941, 876, 825, 674, 638 cm⁻¹.

¹H-NMR(CDCl₃)δ: 1.20(3H, t, J=7.2 Hz), 2.26(3H, s), 2.89-3.00(4H, m),3.35-3.50(5H, m), 3.62(1H, d, J=13.0 Hz), 3.74-3.83(5H, m), 4.12(2H, q,J=7.2 Hz), 4.18(2H, t, J=6.8 Hz), 6.79(2H, d, J=8.4 Hz), 6.95(2H, dd,J=7.3, 7.3 Hz), 7.05(2H, d, J=8.4 Hz), 7.20(2H, dd, J=7.3, 5.0 Hz).

Example 7Methyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2-fluorobenzylamino)propionate(Compound 7)

Referential Compound 3 (208.5 mg) was dissolved in water (15 mL), and a0.5-mol/L aqueous ammonium hydrogencarbonate solution was added theretounder cooling with ice, to thereby adjust the pH of the mixture to 8.The formed aqueous layer was subjected to extraction with ethyl acetate,and the organic layer was dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, to thereby yieldmethyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-aminopropionateas a colorless oil. The product was dissolved in methanol (10 mL), and,while the solution was cooled with ice, 2-fluorobenzaldehyde (79.0 μL)and sodium triacetoxyborohydride (160.1 mg) were added thereto, followedby stirring for 1.5 hours at 0° C. Sodium triacetoxyborohydride (79.9mg) was further added thereto, and the mixture was stirred for 1.5 hoursat 0° C. Acetone (1 mL) was added thereto, and the solvent was removedunder reduced pressure. The thus-obtained crude product was subjected topurification through silica gel column chromatography (ethylacetate:hexane=1:6 to 1:5), to thereby yield 98.8 mg of the titlecompound as a colorless solid.

IRν max(KBr): 3330, 3042, 2958, 2922, 2864, 1723, 1638, 1610, 1585,1552, 1460, 1270, 1245, 1182, 1138, 1056, 1026, 759 cm⁻¹

¹H-NMR(CDCl₃)δ: 2.37(3H, s), 2.97(2H, t, J=6.8 Hz), 2.99(2H, brm),3.57(1H, t, J=6.6 Hz), 3.63(3H, s), 3.83(1H, d, J=13.7 Hz), 3.91(1H, d,J=13.7 Hz), 4.22(2H, t, J=6.8 Hz), 6.81(2H, d, J=6.6 Hz), 6.96-7.10(4H,m), 7.20-7.46(5H, m), 7.96-7.99(2H, m).

Example 8Methyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,4-difluorobenzylamino)propionate(Compound 8)

In the same manner as in Example 7, 243.9 mg of the title compound wasobtained as colorless amorphous compound from 421.3 mg of ReferentialCompound 3 and 240 μL of 2,4-difluorobenzaldehyde.

IRν max(neat): 3338, 3064, 3034, 2951, 2925, 2874, 1736, 1639, 1613,1556, 1512, 1448, 1431, 1337, 1246, 1175, 1138, 1097, 1022, 962, 849,715, 693 cm⁻¹.

¹H-NMR(CDCl₃)δ: 2.37(3H, s), 2.97(2H, t, J=6.5 Hz), 2.95-2.99(2H, m),3.53(1H, t, J=7.5 Hz), 3.65(3H, s), 3.76(1H, d, J=13.4 Hz), 3.85(1H, d,J=13.4 Hz), 4.22(2H, t, J=6.5 Hz), 6.71-6.78(2H, m), 6.81(2H, d, J=8.4Hz), 7.06(2H, d, J=8.4 Hz), 7.26-7.33(1H, m), 7.40-7.43(3H, m),7.96-7.99(2H, m).

Example 9Methyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(3,4-difluorobenzylamino)propionate(Compound 9)

In the same manner as in Example 7, 213.3 mg of the title compound wasobtained as colorless amorphous compound from 490.8 mg of ReferentialCompound 3 and 215 μL of 3,4-difluorobenzaldehyde.

IRν max(neat): 3345, 3061, 3036, 2994, 2951, 2925, 2875, 1734, 1637,1611, 1556, 1514, 1434, 1283, 1246, 1203, 1175, 1114, 1021, 949, 821,776, 715, 693 cm⁻¹.

¹H-NMR(CDCl₃)δ: 2.37(3H, s), 2.97(2H, t, J=6.6 Hz), 2.95-3.12(2H, m),3.54(1H, brs), 3.69(3H, s), 3.69-3.79(1H, m), 3.81(1H, d, J=12.3 Hz),4.22(2H, t, J=6.6 Hz), 6.82(2H, d, J=8.3 Hz), 7.06(2H, d, J=8.3 Hz),6.95-7.18(3H, m), 7.40-7.43(3H, m), 7.96-7.99(2H, m).

Example 10Methyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,3-difluorobenzylamino)propionate(Compound 10)

In the same manner as in Example 7, 253.2 mg of the title compound wasobtained as colorless oil from 510.0 mg of Referential Compound 3 and191 μL of 2,3-difluorobenzaldehyde.

IRν max(neat): 3337, 3034, 2951, 2925, 2874, 1733, 1636, 1612, 1556,1513, 1488, 1448, 1338, 1284, 1246, 1175, 1142, 1022, 949, 825, 776,716, 693 cm⁻¹.

¹H-NMR(CDCl₃)δ: 2.37(3H, s), 2.97(2H, t, J=6.6 Hz), 2.88-2.99(2H, m),3.51(1H, t, J=6.7 Hz), 3.65(3H, s), 3.79(1H, d, J=13.7 Hz), 3.89(1H, d,J=13.7 Hz), 4.22(2H, t, J=6.6 Hz), 6.81(2H, d, J=8.5 Hz), 6.97-7.07(3H,m), 7.05(2H, d, J=8.5 Hz), 7.39-7.46(3H, m), 7.96-7.99(2H, m).

Example 11Methyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,6-difluorobenzylamino)propionate(Compound 11)

In the same manner as in Example 7, 570.3 mg of the title compound wasobtained as colorless powder from 600.8 mg of Referential Compound 3 and220 μL of 2,6-difluorobenzaldehyde.

IRν max(KBr): 3351, 3069, 2955, 2923, 2899, 2873, 1725, 1640, 1626,1590, 1552, 1514, 1469, 1438, 1387, 1337, 1303, 1267, 1234, 1202, 1183,1136, 1071, 1055, 1027, 981, 896, 817, 803, 787, 774, 709, 691, 670, 622cm⁻¹.

¹H-NMR(CDCl₃)δ: 2.36(3H, s), 2.90-3.00(4H, m), 3.51(1H, t, J=6.9 Hz),3.57(3H, s), 3.88(2H, s), 4.21(2H, t, J=6.6 Hz), 6.78(2H, d, J=8.4 Hz),6.84(2H, d, J=7.8 Hz), 7.02(2H, d, J=8.4 Hz), 7.14-7.22(1H, m),7.38-7.46(3H, m), 7.95-8.00(2H, m).

Example 12Methyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,4,6-trifluorobenzylamino)propionate(Compound 12)

In the same manner as in Example 7, 351.5 mg of the title compound wasobtained as pale yellow amorphous compound from 421.3 mg Referentialcompound 3 and 274 mg of 2,4,6-trifluorobenzaldehyde.

IRν max(KBr): 3066, 2952, 2874, 1734, 1717, 1645, 1625, 1608, 1557,1512, 1338, 1246, 1173, 1118, 1062, 1027, 998, 841, 776, 717, 693, 617cm⁻¹.

¹H-NMR(CDCl₃)δ: 2.37(3H, s), 2.97(2H, t, J=6.6 Hz), 2.95-2.99(1H, m),3.54(1H, brs), 3.61(3H, s), 3.85(2H, brs), 4.21(2H, t, J=6.6 Hz),4.73(1H, brs), 6.61(1H, t, J=8.0 Hz), 6.68(1H, t, J=8.0 Hz), 6.80(2H, d,J=8.4 Hz), 7.04(2H, d, J=8.4 Hz), 7.41-7.43(3H, m), 7.97-7.99 (2H, m).

Example 13Methyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(pentafluorobenzylamino)propionate(Compound 13)

In the same manner as in Example 7, 433.0 mg of the title compound wasobtained as colorless oil from 591.2 mg of Referential Compound 3 and250 μL of pentafluorobenzaldehyde.

IRν max(neat): 3348, 2952, 1732, 1652, 1614, 1557, 1507, 1472, 1455,1338, 1299, 1245, 1129, 1021, 946, 831, 776, 716, 694 cm⁻¹.

¹H-NMR(CDCl₃)δ: 2.38(3H, s), 2.84-3.04(2H, m), 2.99(2H, t, J=6.6 Hz),3.46-3.52(1H, m), 3.65(3H, s), 3.84(1H, d, J=12.8 Hz), 3.92(1H, d,J=12.8 Hz), 4.22(2H, t, J=6.6 Hz), 6.79(2H, d, J=8.6 Hz), 7.02(2H, d,J=8.6 Hz), 7.39-7.46(3H, m), 7.97-8.02(2H, m).

Example 14Methyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-chlorobenzylamino)propionate(Compound 14)

In the same manner as in Example 7, 116.4 mg of the title compound wasobtained as colorless powder from 208.6 mg of Referential Compound 3 and104.8 mg of 4-chlorobenzaldehyde.

IRν max(KBr): 3451, 3336, 3060, 3023, 2986, 2950, 2925, 2865, 1732,1643, 1612, 1556, 1513, 1489, 1471, 1448, 1337, 1298, 1246, 1174, 1141,1089, 1068, 1015, 819, 775, 715, 693 cm⁻¹.

¹H-NMR(CDCl₃)δ: 2.37(3H, s), 2.97(2H, t, J=6.8 Hz), 2.99(2H, brm),3.52(1H, brm), 3.66-3.84(5H, m), 4.22(2H, t, J=6.8 Hz), 6.81(2H, d,J=8.6 Hz), 7.06(2H, d, J=8.6 Hz), 7.19-7.24(4H, m), 7.39-7.45(3H, m),7.96-7.99(2H, m).

Example 15Methyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2-chlorobenzylamino)propionate(Compound 15)

In the same manner as in Example 7, 466.5 mg of the title compound wasobtained as colorless oil from 609.3 mg of Referential Compound 3 and230 μL of 2-chlorobenzaldehyde.

IRν max(neat): 3339, 3060, 2950, 1732, 1644, 1613, 1556, 1508, 1472,1338, 1245, 1171, 1036, 948, 897, 831, 754, 716, 693 cm⁻¹.

¹H-NMR(CDCl₃)δ: 2.37(3H, s), 2.94-3.04(4H, m), 3.56(1H, t, J=6.6 Hz),3.64(3H, s), 3.85(1H, d, J=14.3 Hz), 3.96(1H, d, J=14.3 Hz), 4.21(2H, t,J=6.7 Hz), 6.81(2H, d, J=8.6 Hz), 7.07(2H, d, J=8.6 Hz), 7.15-7.21(2H,m), 7.27-7.31(1H, m), 7.32-7.45(4H, m), 7.94-7.99(2H, m).

Example 16Methyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-bromobenzylamino)propionate(Compound 16)

In the same manner as in Example 7, 188.0 mg of the title compound wasobtained as colorless powder from 208.6 mg Referential Compound 3 and138.9 mg of 4-bromobenzaldehyde.

IRν max(KBr): 3339, 3060, 3023, 2949, 2921, 1733, 1646, 1609, 1557,1509, 1488, 1246, 1172, 1135, 1011, 827, 693 cm⁻¹.

¹H-NMR(CDCl₃)δ: 2.38(3H, s), 2.93-3.00(4H, m), 3.49(1H, t, J=6.6 Hz),3.63(1H, d, J=13.4 Hz), 3.66(3H, s), 3.78(1H, d, J=13.4 Hz), 4.22(2H, t,J=6.6 Hz), 6.81(2H, d, J=8.6 Hz), 7.05(2H, d, J=8.6 Hz), 7.13(2H, d,J=8.4 Hz), 7.37-7.45(5H, m), 7.95-7.99(2H, m).

Example 17Ethyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-[N-(4-fluorobenzyl)-N-methylamino]propionate(Compound 17)

Under argon atmosphere, 60% sodium hydride (30 mg) was added at 0° C. toa solution of Compound 1 (253.8 mg) in tetrahydrofuran (5 mL), and themixture was stirred for 30 minutes at room temperature. Under coolingwith ice, methyl iodide (0.16 mL) was added thereto, and the resultantmixture was stirred for 88 hours at room temperature. Water was added tothe reaction mixture, and the solvent was distilled off. The residue wassubjected to extraction with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, and the resultant crudeproduct was subjected to purification through silica gel columnchromatography (ethyl acetate-hexane=1:4 to 1:2), to thereby yield 139.3mg of the title compound as a colorless oil.

IRν max(neat): 3060, 2929, 1728, 1638, 1609, 1556, 1509, 1473, 1449,1370, 1338, 1296, 1245, 1220, 1177, 1155, 1069, 1027, 948, 825, 775,715, 693 cm⁻¹.

¹H-NMR(CDCl₃)δ: 1.23(3H, t, J=7.1 Hz), 2.28(3H, s), 2.37(3H, s),2.87(1H, dd, J=13.7, 7.1 Hz), 2.97(2H, t, J=6.9 Hz), 2.97-3.06(1H, m),3.48(1H, t, J=7.1 Hz), 3.56(1H, d, J=13.7 Hz), 3.75(1H, d, J=13.7 Hz),4.07-4.19(2H, m), 4.22(2H, t, J=6.9 Hz), 6.80(2H, d, J=8.6 Hz), 6.91(2H,d, J=8.6 Hz), 7.04(2H, d, J=8.6 Hz), 7.11(2H, dd, J=8.6, 5.6 Hz),7.37-7.45(3H, m), 7.95-8.00(2H, m).

Example 18(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicAcid (Compound 18)

Compound 1 (1.88 g) was dissolved in ethanol (40 mL), and the solutionwas cooled to 0° C. A 10-%(w/v) aqueous sodium hydroxide solution (4.0mL) was added thereto, and the mixture was stirred overnight, while thetemperature of the mixture was allowed to rise spontaneously. Ethanolwas evaporated, and the residue was diluted with water. Subsequently,1.0-mol/L hydrochloric acid was added dropwise to the resultantsolution, to thereby adjust the pH of the mixture to 5 to 6. Theobtained crude product was washed with diethyl ether and water anddried, to thereby yield 1.58 g of the title compound as a colorlesspowder.

IRν max(KBr): 3422, 3060, 3014, 2949, 2921, 1610, 1514, 1423, 1395,1330, 1250, 1181, 1023, 824 cm⁻¹.

¹H-NMR(DMSO-d₆)δ: 2.36(3H, s), 2.71-2.88(3H, m), 2.92(2H, t, J=6.6 Hz),3.59(1H, d, J=13.7 Hz), 3.75(1H, d, J=13.7 Hz), 4.20(2H, t, J=6.6 Hz),6.83(2H, d, J=8.4 Hz), 7.06-7.12(4H, m), 7.25(2H, dd, J=8.0, 5.6 Hz),7.45-7.48(3H, m), 7.85-7.92(2H, m).

m/z(ESI−): 473(M−H)⁻.

mp.: 184.5-186.5° C.

[α]_(D) ²⁷ (CH₃CO₂H): +21.3 (c=1.0)

Optical purity was determined through HPLC (CHIRALCEL OD-H (product ofDaicel), 25° C., 1 mL/min, 279 nm, n-hexane/ethanol/trifluoroaceticacid=90/10/0.1, (R) compound: 8.19 min, (S) compound: 14.71 min) (98.64%ee).

Example 19(S)-3-[4-[2-[2-(4-Fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicAcid (Compound 19)

In the same manner as in Example 18, 186.0 mg of the title compound wasobtained as colorless powder from 224.9 mg of Compound 2.

IRν max(KBr): 3414, 3070, 2934, 2409, 1608, 1515, 1498, 1247, 1178,1157, 1100, 1021, 843, 816, 742 cm⁻¹.

¹H-NMR(CD₃CO₂D)δ: 2.31(3H, s), 2.90-3.00(2H, m), 3.08-3.18(2H, m),4.08-4.18(3H, m), 4.19-4.33(2H, m), 6.71(2H, d, J=8.3 Hz), 6.92-7.17(6H,m), 7.26-7.35(2H, m), 7.87-7.96(2H, m).

m/z(ESI−): 491(M−H)⁻.

mp.: 191-193° C.

[α]_(D) ²⁸(CH₃CO₂H): +32.6(c=0.20)

Example 20(S)-3-[4-[2-[5-Methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicAcid (Compound 20)

In the same manner as in Example 18, 136.9 mg of the title compound wasobtained as colorless powder from 188.0 mg of Compound 3.

IRν max(KBr): 3404, 3042, 2927, 2872, 2734, 2418, 1607, 1571, 1514,1421, 1380, 1329, 1247, 1176, 1143, 1111, 1078, 1060, 1020, 898, 828,769, 729, 642 cm⁻¹.

¹H-NMR(CD₃CO₂D)δ: 2.27(3H, s), 2.29(3H, s), 2.90-2.98(2H, m),3.16-3.24(2H, m), 4.05-4.30(5H, m), 6.71(2H, d, J=8.1 Hz), 6.96(2H, dd,J=8.1, 8.1 Hz), 7.05(2H, d, J=7.4 Hz), 7.18(2H, d, J=8.1 Hz),7.32-7.42(2H, m), 7.77(2H, d, J=8.1 Hz).

m/z(ESI−): 487(M−H)⁻.

mp.: 196-198° C.

[α]_(D) ²⁷(CH₃CO₂H): +19.3(c=0.23)

Example 21(S)-3-[4-[2-[5-Methyl-2-(4-trifluoromethylphenyl)-1,3-oxazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicAcid (Compound 21)

In the same manner as in Example 18, 204.2 mg of the title compound wasobtained as colorless powder from 225.0 mg of Compound 4.

IRν max(KBr): 3393, 3042, 2937, 2734, 2637, 2409, 1617, 1514, 1414,1388, 1326, 1248, 1167, 1124, 1082, 1064, 1015, 950, 899, 848, 820, 766,714, 688, 670, 620 cm⁻¹.

¹H-NMR(CD₃CO₂D)δ: 2.35(3H, s), 2.93-3.02(2H, m), 3.18-3.37(2H, m),4.10-4.36(5H, m), 6.71-6.78(2H, m), 6.95-7.05(2H, m), 7.06-7.19(2H, m),7.36-7.52(2H, m), 7.70(2H, d, J=8.3 Hz), 8.07(2H, d, J=8.3 Hz).

m/z(ESI−): 541(M−H)⁻.

mp.: 202-204° C.

[α]_(D) ²⁸(CH₃CO₂H): +21.2(c=0.20)

Example 22(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicAcid (Compound 22)

In the same manner as in Example 18, 134.7 mg of the title compound wasobtained as colorless powder from 160.3 mg of Compound 5.

IRν max(KBr): 3423, 3057, 2920, 2864, 2548, 2409, 1595, 1513, 1422,1339, 1305, 1247, 1180, 1113, 1021, 970, 874, 819, 762, 689 cm⁻¹.

¹H-NMR(CD₃CO₂D)δ: 2.46(3H, s), 3.20-3.32(4H, m), 4.20-4.35(5H, m),6.72-6.79(2H, m), 6.96-7.06(2H, m), 7.07-7.15(2H, m), 7.38-7.49(5H, m),7.85-7.92(2H, m).

m/z(ESI−): 489(M−H)⁻.

mp.: 192-195° C.

[α]_(D) ²⁸(CH₃CO₂H): +19.4(c=0.54)

Example 23(S)-3-[4-[2-[5-Methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicAcid (Compound 23)

In the same manner as in Example 18, 111.1 mg of the title compound wasobtained as colorless powder from 147.3 mg of Compound 6.

IRν max(KBr): 3393, 2958, 2919, 2856, 2734, 2604, 2409, 1617, 1578,1511, 1449, 1375, 1324, 1302, 1268, 1226, 1176, 1116, 1064, 1025, 941,898, 819, 764, 714, 671, 630 cm⁻¹.

¹H-NMR(CD₃CO₂D)δ: 2.22(3H, s), 3.00-3.22(4H, m), 3.57-3.84(8H, m),4.10-4.27(4H, m), 4.30(1H, d, J=12.8 Hz), 6.67-6.76(2H, m),6.95-7.15(4H, m), 7.32-7.48(2H, m).

m/z(ESI−): 498(M−H)⁻.

mp.: 192-194° C.

[α]_(D) ²⁸ (CH₃CO₂H): +19.6(c=0.21)

Example 24(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2-fluorobenzylamino)propionicAcid (Compound 24)

In the same manner as in Example 18, 75.8 mg of the title compound wasobtained as colorless powder from 94.9 mg of Compound 7.

IRν max(KBr): 3414, 3060, 3033, 2930, 1618, 1513, 1459, 1423, 1386,1339, 1302, 1249, 1181, 1107, 1069, 1023, 875, 827, 760, 692 cm⁻¹.

¹H-NMR(CD₃CO₂D)δ: 2.36(3H, s), 2.99(2H, t, J=6.2 Hz), 3.20(2H, d, J=5.1Hz), 4.15(2H, t, J=6.2 Hz), 4.27(1H, d, J=12.7 Hz), 4.29(1H, t, J=5.1Hz), 4.39(1H, d, J=12.7 Hz), 6.76(2H, d, J=7.7 Hz), 7.00-7.13(4H, m),7.34-7.43(5H, m), 7.92-7.94(2H, m).

m/z(ESI−): 473(M−H)⁻.

mp.: 191-193° C.

[α]_(D) ²⁷ (CH₃CO₂H): +29.5(c=0.05).

Example 25(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,4-difluorobenzylamino)propionicAcid (Compound 25)

In the same manner as in Example 18, 208.8 mg of the title compound wasobtained as colorless powder from 230.0 mg of Compound 8.

IRν max(KBr): 3385, 3042, 2927, 2871, 1603, 1512, 1432, 1388, 1339,1281, 1250, 1180, 1142, 1101, 1068, 1021, 971, 846, 775, 715, 691 cm⁻¹.

¹H-NMR(DMSO-d₆)δ: 2.35(3H, s), 2.72-2.85(2H, m), 2.90(2H, t, J=6.4 Hz),3.24-3.31(1H, m), 3.59(1H, d, J=14.0 Hz), 3.74(1H, d, J=14.0 Hz),4.17(2H, t, J=6.4 Hz), 6.82(2H, d, J=8.2 Hz), 6.97(1H, dd, J=8.2, 8.2Hz), 7.08(2H, d, J=8.2 Hz), 7.07-7.16(1H, m), 7.33(1H, ddd, J=8.2, 8.2,8.2 Hz), 7.47-7.49(3H, m), 7.89-7.91(2H, m).

m/z(ESI−): 491(M−H)⁻.

mp.: 190-192° C.

[α]_(D) ²⁹(CH₃CO₂H): +43.5(c=0.21)

Example 26(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(3,4-difluorobenzylamino)propionicAcid (Compound 26)

In the same manner as in Example 18, 179.2 mg of the title compound wasobtained as colorless powder from 211.0 mg of Compound 9.

IRν max(KBr): 3050, 2929, 2871, 1607, 1560, 1525, 1513, 1447, 1387,1332, 1291, 1250, 1176, 1146, 1125, 1068, 1019, 816, 776, 718, 691, 627cm⁻¹.

¹H-NMR(DMSO-d₆)δ: 2.35(3H, s), 2.73-2.82(2H, m), 2.90(2H, t, J=6.4 Hz),3.18-3.21(1H, m), 3.56(1H, d, J=14.1 Hz), 3.75(1H, d, J=14.1 Hz),4.17(2H, t, J=6.4 Hz), 6.83(2H, d, J=8.3 Hz), 7.00-7.08(1H, m), 7.09(2H,d, J=8.3 Hz), 7.15-7.30(2H, m), 7.47-7.49(3H, m), 7.89-7.91(2H, m).

m/z(ESI−): 491(M−H)⁻.

mp.: 202-204° C.

[α]_(D) ²⁹ (CH₃CO₂H): +44.2(c=0.10)

Example 27(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,3-difluorobenzylamino)propionicAcid (Compound 27)

In the same manner as in Example 18, 213.8 mg of the title compound wasobtained as colorless powder from 250.0 mg of Compound 10.

IRν max(KBr): 3406, 3037, 2929, 2872, 2744, 2670, 2540, 2416, 1626,1514, 1491, 1431, 1389, 1329, 1291, 1249, 1201, 1183, 1083, 1067, 1022,832, 792, 736, 711, 691 cm⁻¹.

¹H-NMR(CD₃CO₂D)δ: 2.36(3H, s), 2.99(2H, t, J=6.0 Hz), 3.30(2H, d, J=5.8Hz), 4.16(2H, t, J=6.0 Hz), 4.36(1H, t, J=5.8 Hz), 4.41(2H, s), 6.77(2H,d, J=8.2 Hz), 7.10-7.27(2H, m), 7.14(2H, d, J=8.2 Hz), 7.19-7.43(4H, m),7.94-7.95(2H, m).

m/z(ESI−): 491(M−H)⁻.

mp.: 173-175° C.

[α]_(D) ²⁹(CH₃CO₂H): +27.0(c=1.1)

Example 28(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,6-difluorobenzylamino)propionicAcid (Compound 28)

In the same manner as in Example 18, 453.7 mg of the title compound wasobtained as colorless powder from 530.4 mg of Compound 11.

IRν max(KBr): 3421, 3032, 2925, 2632, 1718, 1629, 1553, 1512, 1473,1388, 1339, 1247, 1179, 1070, 1024, 826, 787, 717, 692 cm⁻¹.

¹H-NMR(CD₃CO₂D)δ: 2.49(3H, s), 3.14-3.25(2H, m), 3.33-3.54(2H, m),4.25-4.37(2H, m), 4.40-4.58(3H, m), 6.85(2H, d, J=6.9 Hz), 6.94-7.05(2H,m), 7.25(2H, d, J=6.9 Hz), 7.40-7.52(1H, m), 7.53-7.66(3H, m),8.16-8.24(2H, m).

m/z(ESI−): 491(M−H)⁻.

mp.: 165-167° C.

[α]_(D) ²⁹ (CH₃CO₂H): +39.5(c=0.21)

Example 29(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,4,6-trifluorobenzylamino)propionicAcid (Compound 29)

In the same manner as in Example 18, 189.1 mg of the title compound wasobtained as colorless powder from 351.5 mg of Compound 12.

IRν max(KBr): 3174, 3016, 2933, 1610, 1555, 1510, 1449, 1340, 1243,1211, 1184, 1123, 1082, 1009, 833, 772, 711, 688 cm⁻¹.

¹H-NMR(DMSO-d₆)δ: 2.34(3H, s), 2.71(1H, dd, J=13.6, 7.0 Hz), 2.78(1H,dd, J=13.6, 7.0 Hz), 2.90(2H, t, J=6.5 Hz), 3.26(1H, dd, J=7.0, 7.0 Hz),3.61(1H, d, J=13.0 Hz), 3.71(1H, d, J=13.0 Hz), 4.16(2H, t, J=6.5 Hz),6.79(2H, d, J=8.2 Hz), 7.04(2H, d, J=8.2 Hz), 7.10(2H, t, J=8.1 Hz),7.47-7.49(3H, m), 7.89-7.91(2H, m)

m/z(ESI−): 509(M−H)⁻.

mp.: 168-170° C.

[α]_(D) ²⁹(CH₃CO₂H): +32.3(c=0.30)

Example 30(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(pentafluorobenzylamino)propionicAcid (Compound 30)

In the same manner as in Example 18, 328.4 mg of the title compound wasobtained as colorless powder from 431.0 mg of Compound 13.

IRν max(KBr): 3395, 3060, 2941, 2874, 1609, 1509, 1448, 1336, 1296,1248, 1178, 1137, 1068, 1015, 982, 937, 833, 773, 716, 689 cm⁻¹.

¹H-NMR(DMSO-d₆)δ: 2.35(3H, s), 2.60-2.70(1H, m), 2.72-2.82(1H, m),2.90(2H, t, J=6.6 Hz), 3.18-3.22(1H, m), 3.71(1H, d, J=13.0 Hz),3.80(1H, d, J=13.0 Hz), 4.15(2H, t, J=6.6 Hz), 6.77(2H, d, J=8.2 Hz),7.04(2H, d, J=8.2 Hz), 7.47-7.52(3H, m), 7.87-7.94(2H, m).

m/z(ESI−): 545(M−H)⁻.

mp.: 156-158° C.

[α]_(D) ²⁹(CH₃CO₂H): +24.2(c=0.24)

Example 31(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-chlorobenzylamino)propionicAcid (Compound 31)

In the same manner as in Example 18, 73.7 mg of the title compound wasobtained as colorless powder from 112.7 mg of Compound 14.

IRν max(KBr): 3423, 3060, 2930, 2865, 2735, 2642, 1609, 1513, 1491,1448, 1386, 1333, 1249, 1181, 1107, 1088, 1061, 1013 cm⁻.

¹H-NMR(CD₃CO₂D)δ: 2.35(3H, s), 2.98(2H, t, J=6.2 Hz), 3.13-3.17(2H, m),4.11-4.17(3H, m), 4.35(2H, m), 6.74(2H, d, J=8.3 Hz), 7.61(2H, d, J=8.3Hz), 7.28(4H, s), 7.39-7.42(3H, m), 7.90-7.94(2H, m).

m/z(ESI−) 489(M−H)⁻, 491(M−H)⁻.

mp.: 197-199° C.

[α]_(D) ²⁶ (CH₃CO₂H): +44.0(c=0.06)

Example 32(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2-chlorobenzylamino)propionicAcid (Compound 32)

In the same manner as in Example 18, 365.5 mg of the title compound wasobtained as colorless powder from 406.5 mg of Compound 15.

IRν max(KBr): 3395, 3060, 3032, 2920, 2864, 1609, 1511, 1447, 1387,1339, 1296, 1249, 1177, 1060, 1021, 830, 754, 716, 690 cm⁻¹.

¹H-NMR(CD₃CO₂D)δ: 2.35(3H, s), 2.99(2H, t, J=5.6 Hz), 3.26-3.35(2H, m),4.17(2H, t, J=5.6 Hz), 4.30-4.52(3H, m), 6.78(2H, d, J=7.7 Hz), 7.14(2H,d, J=7.7 Hz), 7.21-7.37(3H, m), 7.38-7.45(3H, m), 7.59-7.70(1H, m),7.90-7.98(2H, m).

m/z(ESI−): 489(M−H)⁻, 491(M−H)⁻.

mp.: 143-145° C.

[α]_(D) ²⁹(CH₃CO₂H): +15.1(c=0.21)

Example 33(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-bromobenzylamino)propionicAcid (Compound 33)

In the same manner as in Example 18, 152.3 mg of the title compound wasobtained as colorless powder from 185.9 mg of Compound 16.

IRν max(KBr): 3423, 3051, 2931, 2865, 1608, 1513, 1490, 1451, 1388,1333, 1249, 1178, 1070, 1016, 837, 799, 716, 691 cm⁻¹.

¹H-NMR(CD₃CO₂D)δ: 2.35(3H, s), 2.98(2H, t, J=6.1 Hz), 3.12-3.16(2H, m),4.09-4.16(3H, m), 4.24(1H, t, J=5.9 Hz), 4.31(1H, d, J=13.4 Hz),6.74(2H, d, J=8.4 Hz), 7.05(2H, d, J=8.4 Hz), 7.22(2H, d, J=8.4 Hz),7.39-7.44(5H, m), 7.90-7.93(2H, m).

m/z(ESI−): 533(M−H)⁻, 535(M−H)⁻.

mp.: 196-199° C.

[α]_(D) ²⁷ (CH₃CO₂H): +35.5(c=0.09)

Example 34(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-[N-(4-fluorobenzyl)-N-methylamino]propionicAcid (Compound 34)

In the same manner as in Example 18, 105.6 mg of the title compound wasobtained as colorless powder from 163.3 mg of Compound 17.

IRν max(KBr): 3422, 3042, 2923, 2237, 1609, 1510, 1449, 1351, 1285,1246, 1225, 1175, 1108, 1018, 855, 828, 765, 714, 691, 647 cm⁻¹.

¹H-NMR(DMSO-d₆)δ: 2.18(3H, s), 2.36(3H, s), 2.79(1H, dd, J=13.7, 7.7Hz), 2.88-2.97(3H, m), 3.32-3.45(1H, m), 3.55(1H, d, J=13.3 Hz),3.71(1H, d, J=13.3 Hz), 4.19(2H, t, J=6.4 Hz), 6.83(2H, d, J=8.4 Hz),7.01(2H, d, J=8.4 Hz), 7.05-7.15(4H, m), 7.45-7.52(3H, m), 7.88-7.93(2H,m).

m/z(ESI−): 487(M−H)⁻.

mp.: 142-145° C.

[α]_(D) ³²(CH₃OH): +13.6(c=0.58)

Example 35 Sodium(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionate(Compound 35)

Compound 18 (1.57 g) was suspended in methanol (30 mL), and sodiummethoxide was added to the resultant mixture until an substantiallyhomogeneous solution was obtained. The solution was filtered, and thefiltrate was concentrated. Diethyl ether was added thereto, and theresultant colorless crystals were collected through filtration and driedunder reduced pressure, to thereby yield 1.57 g of the title compound.

IRν max(KBr): 3422, 3060, 3033, 2921, 2865, 1590, 1510, 1451, 1398,1339, 1247, 1172, 1116, 1023, 824 cm⁻¹.

¹H-NMR(DMSO-d₆)δ: 2.36(3H, s), 2.75-2.86(3H, m), 2.91(2H, t, J=6.6 Hz),3.35(1H, d, J=13.5 Hz), 3.55(1H, d, J=13.5 Hz), 4.17(2H, t, J=6.6 Hz),6.77(2H, d, J=8.3 Hz), 7.00-7.20(6H, m), 7.45-7.51(3H, m), 7.88-7.93(2H,m).

m/z(ESI−): 473(M−Na)⁻.

mp.: 179-181° C.

[α]_(D) ³⁰(CH₃OH): +7.7(c=1.1)

Example 36(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicAcid Hydrochloride (Compound 36)

Under argon atmosphere, hydrogen chloride gas was introduced into asolution of Referential Compound 2 (187.4 mg) in ethyl acetate (3 mL)for 0.5 hours at 0° C. The solvent was removed under reduced pressure,and the resultant crude product was washed with diethyl ether and driedunder reduced pressure, to thereby yield 142.6 mg of the title compoundas a colorless amorphous compound.

IRν max(KBr): 3386, 2930, 2775, 1736, 1677, 1608, 1513, 1438, 1376,1248, 1227, 1181, 1028, 953, 837, 778, 715, 687 cm⁻¹.

¹H-NMR(DMSO-d₆)δ: 2.35(3H, s), 2.91(2H, t, J=6.6 Hz), 3.03(1H, dd,J=14.1, 8.4 Hz), 3.30(1H, dd, J=14.1, 4.3 Hz), 4.05-4.16(3H, m),4.18(2H, t, J=6.6 Hz), 6.89(2H, d, J=8.5 Hz), 7.15(2H, d, J=8.5 Hz),7.24(1H, d, J=8.6 Hz), 7.27(1H, d, J=8.6 Hz), 7.47-7.49(3H, m), 7.55(1H,d, J=8.6 Hz), 7.57(1H, d, J=8.6 Hz), 7.89-7.92(2H, m)

m/z(ESI−): 473(M−HCl−H)⁻.

mp.: 198-200° C.

[α]_(D) ²⁹ (CH₃CO₂H): +39.9(c=0.26)

Example 37Ethyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionateHydrochloride (Compound 37)

Compound 1 (256 mg) was dissolved in diethyl ether (5.0 mL), and a1,4-dioxane solution saturated with hydrogen chloride (0.3 mL) was addedthereto, followed by stirring. The produced colorless crystals werecollected through filtration and dried under reduced pressure, tothereby yield 126 mg of the title compound.

IRν max(KBr): 3421, 2930, 2727, 1736, 1608, 1513, 1473, 1448, 1396,1376, 1300, 1248, 1226, 1179, 1162, 1026, 835 cm⁻¹.

¹H-NMR(CDCl₃)δ: 1.17(3H, t, J=6.8 Hz), 2.46(3H, s), 3.15(2H, t, J=6.0Hz), 3.35-3.51(2H, m), 3.82(1H, brs), 4.08-4.31(6H, m), 6.78(2H, d,J=8.5 Hz), 7.02(2H, dd, J=8.5, 8.5 Hz), 7.12(2H, d, J=8.5 Hz),7.51-7.61(5H, m), 8.26(2H, d, J=8.5 Hz).

m/z(ESI+): 503(M−HCl+H)⁺.

mp.: 69-71° C.

[α]_(D) ²⁶ (CHCl₃): +18.2(c=0.50)

Example 38Ethyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionatemethanesulfonate (Compound 38)

Methanesulfonic acid (7.8 mL) was added to a solution of Compound 1(50.2 g) in ethanol (150 mL), and the temperature of the solution waselevated to 40° C. The solution was stirred for 10 minutes, and thereactor was cooled in an ice bath. When the interior temperature reached10° C. or lower, diisopropyl ether (300 mL) was added thereto, and themixture was left to stand for night and day in a dark cold place. Theproduct was collected through filtration with a glass filter and driedunder reduced pressure, to thereby yield 52.1 g of the title compound ascolorless crystals.

IRν max(KBr): 3423, 2957, 2759, 2627, 1742, 1637, 1607, 1224, 1156, 1040cm⁻¹.

¹H-NMR(CDCl₃)δ: 0.98(3H, t, J=7.2 Hz), 2.30(3H, s), 2.35(3H, s),2.88-3.95(4H, m), 3.99(2H, q, J=7.2 Hz), 4.17-4.21(5H, m), 6.90(2H, d,J=8.4 Hz), 7.10(2H, d, J=8.4 Hz), 7.28(2H, dd, J=8.7, 8.7 Hz),7.47-7.54(5H, m), 7.88-7.91(2H, m).

m/z(ESI+): 503(M−CH₃SO₃H+H)⁺.

mp.: 144° C.

[α]_(D) ²⁰(C₂H₅OH): +24.3(c=1.3).

Comparative Example 1(S)-3-[4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(benzylamino)propionicAcid (the Compound Described in Example 27 of WO96/38415, ComparativeCompound 1)

Ethyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(benzylamino)propionatewas synthesized through the method described in WO96/38415, and theproduct (745 mg) was processed, to thereby yield 507 mg of the titlecompound as a colorless powder.

IRν max(KBr): 3422, 3035, 2953, 2870, 1617, 1511, 1438, 1389, 1334,1304, 1247, 1180, 1143, 1113, 1068 cm⁻¹. ¹H-NMR(CD₃OD)δ: 2.36(3H, s),2.99(2H, t, J=6.1 Hz), 3.11-3.22(2H, m), 4.11-4.16(3H, m), 4.23(1H, t,J=6.3 Hz), 4.32(1H, d, J=12.7 Hz), 6.76(2H, d, J=8.1 Hz), 7.07(2H, d,J=8.1 Hz), 7.30-7.42(8H, m), 7.92-7.93(2H, m).

m/z(ESI−): 455(M−H)⁻.

mp.: 206-209° C.

[α]_(D) ²⁹(CH₃CO₂H): +15.5(c=0.49)

Test Example Blood glucose Lowering Effect and Blood Lipid (Blood TG andBlood FFA) Lowering Effect in Mice

Each of the test compounds was suspended in a 0.5-%(w/v) sodium CMCsolution, and the suspension was forcedly administered via oral routeonce a day over seven days to male KKA^(y) mice(obesity/noninsulin-dependent diabetes mellitus model, 6 to 7 weeks old,3 to 5 animals per group) (1 mg/kg/day). During this 7-day period, feedand water were taken ad libitum. On the day following the finaladministration, blood was drawn from the tail vein without anesthesiaand centrifuged, to thereby prepare plasma samples. Plasma glucoselevel, plasma TG level, and plasma FFA level of the samples weredetermined through the enzymatic method by use of an L-type Wako Glu2(Wako Pure Chemical Industries), an L-type Wako TG-H (Wako Pure ChemicalIndustries), and an NEFA-HA Test Wako (Wako Pure Chemical Industries),respectively, by means of a full-automated clinical chemistry analyzer(CL-8000, Shimadzu Corporation). Percent reduction was determined fromthe obtained values by use of the following equations. The results areshown in Table 1.

TABLE 1 Percent reduction Percent Percent of blood reduction reductionglucose of blood of blood level TG level FFA level Compound (%) (%) (%)Compound 18 15 40 27 Compound 20 21 36 25 Compound 22 33 53 36 Compound27 40 48 16 Compound 28 50 65 54 Compound 29 43 74 58 Compound 32 39 3313 Compound 35 36 47 33 Compound 38 25 33 16 Comparative 12 17 −2Compound 1 Percent reduction of blood glucose level (%) = [(Bloodglucose level of the control group − Blood glucose level of the group towhich a test compound is administered)/Blood glucose level of thecontrol group] × 100 Percent reduction of blood TG level (%) = [(BloodTG level of the control group − Blood TG level of the group to which atest compound is administered)/Blood TG level of the control group] ×100 Percent reduction of blood FFA level (%) = [(Blood FFA level of thecontrol group − Blood FFA level of the group to which a test compound isadministered)/Blood FFA level of the control group] × 100

As shown in Table 1, the present compound (1) or a salt thereof wasfound to exhibit not only a blood glucose level lowering effect, butalso remarkably excellent effect of lowering blood lipid (TG and FFA)levels as compared with the compound described in Example 27 ofWO96/38415.

Separately, the present compound (1) or a salt thereof was orallyadministered to KKA^(y) mice over two weeks (0.1, 0.3, or 1 mg/kg/day),and plasma adiponectin level of each mouse was determined. Compound 18was found to exhibit particularly excellent effect of increasing plasmaadiponectin level, indicating that Compound 18 exerts antidiabete andantiarteriosclerosis effects.

Industrial Applicability

The present invention provides a drug which exhibits potent bloodglucose lowering effect and blood lipid lowering effect, and the drug isparticularly useful as a preventive or therapeutic agent for diabetes,hyperlipidemia, impaired glucose tolerance, arteriosclerosis, or similarpathological conditions.

1. A halogenobenzylaminopropionic acid derivative represented by thefollowing formula (1):

wherein each of R¹ and R², which may be identical to or different fromeach other, represents a hydrogen atom or a lower alkyl group; R³represents a phenyl group which may have a substituent, a morpholinylgroup, or a pyridinyl group; X represents a halogen atom; n representsan integer of 1 to 5; and A represents an oxygen atom or a sulfur atom;or a pharmaceutically acceptable salt of the derivative.
 2. Ahalogenobenzylaminopropionic acid derivative as described in claim 1,wherein R¹ is a hydrogen atom, a methyl group, or an ethyl group, R² isa hydrogen atom or a methyl group, R³ is a morpholinyl group or a phenylgroup which may have a substituent, X is a fluorine atom, a chlorineatom, or an bromine atom, and n is an integer of 1 to 3; or apharmaceutically acceptable salt of the derivative.
 3. Ahalogenobenzylaminopropionic acid derivative as described in claim 2,wherein R³ is a phenyl group which may have a substituent and X is afluorine atom or a chlorine atom; or a pharmaceutically acceptable saltof the derivative.
 4. A halogenobenzylaminopropionic acid derivativeselected from the group consisting ofethyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionate,(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicacid,(S)-3-[4-[2-[5-methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicacid,(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicacid,(S)-3-[4-[2-[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]ethoxy]phenyl]-2-(4-fluorobenzylamino)propionicacid,(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,3-difluorobenzylamino)propionicacid,(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,6-difluorobenzylamino)propionicacid,(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2,4,6-trifluorobenzylamino)propionicacid,(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(4-chlorobenzylamino)propionicacid,(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-(2-chlorobenzylamino)propionicacid, and(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-[N-(4-fluorobenzyl)-N-methylamino]propionicacid; or a pharmaceutically acceptable salt of the derivative.
 5. A drugcomposition comprising a halogenobenzylaminopropionic acid derivative ora pharmaceutically acceptable salt of the derivative as recited in anyof claim 1, and a pharmaceutically acceptable carrier.
 6. A method fortreating diabetes and/or hyperlipidemia, which comprises administering,to a subject in need thereof, an effective dose of ahalogenobenzylaminopropionic acid derivative or a pharmaceuticallyacceptable salt of the derivative as recited in claim
 1. 7. A method ofincreasing the plasma adiponectin level which comprises administering,to a subject in need thereof, an effective dose of ethyl(S)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4yl)ethoxyl]phenyl]-2-(4-fluorobenzylamino)propionateacid, or a pharmaceutically acceptable salt thereof.
 8. A method fortreating diabetes and/or hyperlipidemia caused by diabetes, whichcomprises administering, to a subject in need of thereof, an effectivedose of a halogenobenzylaminopropionic acid derivative or apharmaceutically acceptable salt of the derivative as recited in claim1.